TRICOM vector based cancer vaccines

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute/NIH, Bldg. 10, Rm. 8B09, 10 Center Drive, Bethesda, MD 20892, USA.
Current Pharmaceutical Design (Impact Factor: 3.45). 02/2006; 12(3):351-61. DOI: 10.2174/138161206775201929
Source: PubMed


For the immune system to mount an effective antitumor T-cell response, an adequate number of T-cells specific for the antigens expressed by the malignancy must be activated [1]. Since most antigens expressed by tumors are "self"-antigens, tumor antigens often lack endogenous immunogenicity and thus do not sufficiently activate T-cells to levels that can mediate tumor eradication. In addition, virtually all solid tumor cells lack the costimulatory molecules necessary to activate tumor-specific T-cells. Approaches that stimulate immune responses to these tumor antigens have the potential to alter this poor responsiveness. This theory has promoted the use of active immunotherapy to generate immune responses against tumor-associated antigens (TAAs) for the treatment of cancer. As one such vaccine strategy, we have utilized poxviruses as delivery vehicles for TAAs in combination with T-cell costimulatory molecules. Initial studies have demonstrated that the insertion of costimulatory molecule trangenes into viral vectors, along with a TAA transgene, greatly enhances the immune response to the antigen. Using this approach, a TRIad of COstimulatory Molecules (TRICOM; B7-1, ICAM-1 and LFA-3) has been shown to enhance T-cell responses to TAAs to levels far greater than any one or two of the costimulatory molecules in combination. In this article, preclinical findings and recent clinical applications of TRICOM-based vaccines as a cancer immunotherapy are reviewed.

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Available from: Mala Chakraborty
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    • "Those studies indicated that yeast-Twist induced an antitumor immune response in the 4T1 model in the absence of autoimmunity, even though Twist expression was confirmed in normal tissue of BALB/c mice. The yeast and pox-TRICOM platforms have previously been shown to be quite different in terms of the types of T cells and cytokines induced404142. Here we sought to confirm that metastasis-associated transcription factors are suitable targets for vaccinemediated immunotherapy. "
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    ABSTRACT: Several transcription factors play a role in the alteration of gene expression that occurs during cancer metastasis. Twist expression has been shown to be associated with the hallmarks of the metastatic process, as well as poor prognosis and drug resistance in many tumor types. However, primarily due to their location within the cell and the lack of a hydrophobic groove required for drug attachment, transcription factors such as Twist are difficult to target with conventional therapies. An alternative therapeutic strategy is a vaccine comprised of a Modified vaccinia Ankara (MVA), incorporating the Twist transgene and a TRIad of COstimulatory Molecules (B7-1, ICAM-1, LFA-3; TRICOM). Here we characterize an MVA-TWIST/TRICOM vaccine that induced both CD4+ and CD8+ Twist-specific T-cell responses in vivo. In addition, administration of this vaccine reduced both the primary tumor growth and metastasis in the 4T1 model of metastatic breast cancer. In the TRAMP transgenic model of spontaneous prostate cancer, MVA-TWIST/TRICOM alone significantly improved survival, and when combined with the androgen receptor antagonist enzalutamide, the vaccine further improved survival. These studies thus provide a rationale for the use of active immunotherapy targeting transcription factors involved in the metastatic process and for the combination of cancer vaccines with androgen deprivation.
    Preview · Article · Jul 2015 · Oncotarget
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    • "However, DC vaccines loaded with peptides are limited in their application, as they will be effective only in patients with specific HLA subtypes, depending on the TAA epitope chosen. Another DC-based vaccine approach being explored in breast cancer uses viral vectors carrying TAA genes (such as CEA and MUC-1) along with co-stimulatory molecule genes (B7.1, ICAM-1, LFA-3) (8,9). However, since peptide or viral vaccines only target one or two antigens, any surviving tumor cell clones could, theoretically, easily down-regulate the expression of those target antigens and evade the immune response. "
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    ABSTRACT: A dendritic cell (DC)-based vaccine strategy could reduce the risk of recurrence and improve the survival of breast cancer patients. However, while therapy-induced apoptosis of hepatocellular and colorectal carcinoma cells can enhance maturation and antigen presentation of DCs, whether this effect occurs in breast cancer is currently unknown. In the present study, we investigated the effect of doxorubicin (ADM)-induced apoptotic MCF-7 breast cancer cells on the activation of DCs. ADM-induced apoptotic MCF-7 cells could effectively induce immature DC (iDC) maturation. The mean fluorescence intensity (MFI) of DC maturity marker CD83 was 23.3 in the ADM-induced apoptotic MCF-7 cell group compared with 8.5 in the MCF-7 cell group. The MFI of DC co-stimulatory marker CD86 and HLA-DR were also increased after iDCs were treated with ADM-induced apoptotic MCF-7 cells. Furthermore, the proliferating autologous T-lymphocytes increased from 14.2 to 40.3% after incubated with DCs induced by apoptotic MCF-7 cells. The secretion of interferon-γ by these T-lymphocytes was also increased. In addition, cell-cell interaction between apoptotic MCF-7 cells and iDCs, but not soluble factors released by apoptotic MCF-7 cells, was crucial for the maturation of iDCs. These findings constitute a novel in vitro DC-based vaccine strategy for the treatment of breast cancer by ADM-induced apoptotic MCF-7 cells.
    Full-text · Article · Apr 2012 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
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    • "The above examples support a relation between immune suppression (or Th2 deviation) and cancer proliferation, the opposite circumstance, of immune stimulation resulting in anticancer response is also documented. Numerous clinical trials using antigen specific approaches such as vaccination with either tumor antigens alone [33,34], tumor antigens bound to immunogens [35,36], tumor antigens delivered alone [37] or in combination with costimulatory molecules by viral methods [38], tumor antigens loaded on dendritic cells ex vivo [39-41], or administration of in vitro generated tumor-reactive T cells [42], have all demonstrated some, albeit modest clinical effects. It is documented that inappropriate immune responses (broadly speaking Th2 responses) can actually stimulate tumor growth [43,44]. "
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    ABSTRACT: Advances in cancer therapy have been substantial in terms of molecular understanding of disease mechanisms, however these advances have not translated into increased survival in the majority of cancer types. One unsolved problem in current cancer therapeutics is the substantial immune suppression seen in patients. Conventionally, investigations in this area have focused on antigen-nonspecific immune suppressive molecules such as cytokines and T cell apoptosis inducing molecules such as Fas ligand. More recently, studies have demonstrated nanovesicle particles termed exosomes are involved not only in stimulation but also inhibition of immunity in physiological conditions. Interestingly, exosomes secreted by cancer cells have been demonstrated to express tumor antigens, as well as immune suppressive molecules such as PD-1L and FasL. Concentrations of exosomes from plasma of cancer patients have been associated with spontaneous T cell apoptosis, which is associated in some situations with shortened survival. In this paper we place the "exosome-immune suppression" concept in perspective of other tumor immune evasion mechanisms. We conclude by discussing a novel therapeutic approach to cancer immune suppression by extracorporeal removal of exosomes using hollow fiber filtration technology.
    Full-text · Article · Jul 2008 · Journal of Translational Medicine
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